Prediction in Rectal Cancer

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The treatment of rectal cancer largely depends on disease stage at diagnosis, based on which patients can be classified as low, intermediate, or high risk. Prognostic and predictive markers, specific to each risk category, can be applied for optimal risk classification and subsequent treatment allocation. These markers are either histopathological, determined with imaging, or have a biomolecular background. This review provides an overview of the current status of treatment options and the use of prognostic and predictive markers in each risk category. An effort was made to identify those markers that are currently lacking in, but have the potential to improve, the clinical decision process by discussing the data from recent studies aimed at the development of new prognostic and predictive markers. At this moment, none of the markers studied has been proven to be of significant, independent value, justifying implementation in daily clinical practice. However, recent developments in imaging techniques and biomolecular research do show great potential.

Section snippets

The “Good”

The “Good” rectal cancers are T1 or T2, lymph node–negative rectal cancers that, after TME surgery, have very low local recurrence rates and high cure rates.5, 22 More controversial treatment options aimed at rectum preservation with the subsequent improved quality of life include transanal endoscopic microsurgery (TEM) with or without preoperative chemoradiotherapy (CRT) or CRT followed by a wait-and-see policy.23, 24, 25, 26, 27 The question is whether these approaches are safe and feasible

The “Bad”

In general, “bad” or intermediate-risk rectal cancer patients have large T3N0 tumors or a T1-3N1 tumor and will be treated with preoperative RT followed by TME surgery or in the case of a threatened or involved mesorectal fascia, with preoperative CRT. The choice between preoperative CRT and short-course (SC) RT is still a subject of debate. Two randomized studies compared preoperative CRT with SC (5 × 5 Gy) RT, but were underpowered to evaluate the effect on local control.37, 38 Early

The “Ugly”

“Ugly” tumors have a high risk of local and distant recurrence and features such as T4 stage and extensive lymph node involvement. Survival improvement might be achieved by response-based treatment adaptation and the addition of targeted therapies with radiosensitizing potential. Two of these strategies use epidermal growth factor receptor (EGFR) inhibitors, such as cetuximab, and inhibitors of the glycoprotein vascular endothelial growth factor, such as bevacizumab.8, 39, 40, 41 The results of

Current Developments in Prediction

With the introduction of more organ-saving procedures, intensification of treatment, and the awareness of negative side effects of treatment, the call for both prognostic and predictive markers is unmistakable. With a local recurrence rate of approximately 6% to 10% for most rectal cancer patients, the number needed to treat of preoperative RT to prevent one local recurrence (LR) varies between 10 and 18 patients. A subgroup of patients with “good” tumors has an LR risk of <4%, and limited

Prognostic Markers

Prognostic markers are markers that predict clinical outcome, that is, the chance of developing a local or distant recurrence. In rectal cancer, prognostic markers also comprise preoperative markers that predict tumor extent and nodal involvement, as these determine treatment of the primary tumor. Prognostic markers in rectal cancer are based on imaging and histopathology and, in the near future, also on molecular markers. Each type of marker will be discussed in this article.

Preoperative Imaging in Rectal Cancer

Instead of T-stage, the actual distance of the tumor to the mesorectal fascia has repeatedly been shown to be a more important factor for LR because T-stage does not discriminate between tumors that can be easily resected and tumors with a high chance of CRM involvement. So far, MRI has been the only imaging modality that has been found useful for the prediction of the CRM. A recent meta-analysis of several single-center studies demonstrated that the sensitivity varies between 60% and 88%, with

Histopathological Evaluation

The local tumor extent is traditionally classified through the pathologic T-staging system, with T3 and T4 tumors being considered to have the highest risk of LR. Also, nodal involvement and CRM involvement can be reliably determined by histopathology. Lymphovascular invasion, extramural venous invasion, serosal involvement, and poor differentiation are other factors related to an increased local recurrence risk.56 The depth of extramural disease and the presence of extramural venous invasion

Molecular Markers

Until now, not many prognostic molecular markers have been identified that are specific for rectal cancer patients. The majority of the data on prognostic molecular markers come from studies including both colon and rectal cancer (CRC) patients. Within these CRC series, the predictive and prognostic roles of several molecular markers involved in proliferation, apoptosis, neoangiogenesis, DNA mismatch repair, and 5-fluorouracil metabolism have been investigated.60, 61, 62, 63 In addition,

Predictive Markers

Comparable with prognostic markers, predictive factors can be derived from histopathological studies, imaging modalities, or molecular markers. A recent review concluded that conventional histopathologically based indices, such as tumor stage and grade, were not sufficiently capable of predicting response to CRT.95 Treatment response prediction with imaging techniques shows more promising results.96 However, staging accuracy is reduced after preoperative treatment compared with nontreated

Technical Problems and Logistics

The fact that none of these biomarkers is currently used in the clinical setting is probably not only because of a lack of relevance or reproducibility. Several other factors hamper the implementation of these markers. Ideally, the optimal moment to determine the status of a predictive marker would be on pretreatment biopsies. Unfortunately, for research purposes, pretreatment biopsies are often not available or are very small. In post-treatment samples, (nearly) complete tumor regression or

Future Directives

Future initiatives should be aimed at the incorporation of prognostic and predictive markers derived from preoperative imaging, histopathological studies as well as molecular studies into one “tool.” To be able to base treatment decisions on this tool, it should be effective in determining disease stage and outcome, as well as easily applicable in current clinical practice. At this moment, the best example of such a comprehensive application has been developed by Valentini et al.115 A model to

Conclusions

The development of additional and alternative treatment strategies to standard TME surgery has increased the need for better patient selection. Nowadays, patient selection for treatment is a balanced process of weighing the pros and cons of each modality. This patient-tailored approach demands the availability of reliable information about CRM and lymph node involvement, biological tumor behavior, and the expected response to treatment. The future of the implementation of new treatment

References (115)

  • J.P. Machiels et al.

    Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer

    Ann Oncol

    (2007)
  • C. Rödel et al.

    Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer

    Int J Radiat Oncol Biol Phys

    (2008)
  • C. Weiss et al.

    Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: A pooled analysis of three prospective phase I-II trials

    Int J Radiat Oncol Biol Phys

    (2010)
  • J.M. Ebos et al.

    Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis

    Cancer Cell

    (2009)
  • M. Pàez-Ribes et al.

    Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis

    Cancer Cell

    (2009)
  • M.J. Lahaye et al.

    Imaging for predicting the risk factors—The circumferential resection margin and nodal disease—Of local recurrence in rectal cancer: A meta-analysis

    Semin Ultrasound CT MR

    (2005)
  • R.C. Dresen et al.

    Local recurrence in rectal cancer can be predicted by histopathological factors

    Eur J Surg Oncol

    (2009)
  • M. Maas et al.

    Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: A pooled analysis of individual patient data

    Lancet Oncol

    (2010)
  • B.D. O'Neill et al.

    Non-operative treatment after neoadjuvant chemoradiotherapy for rectal cancer

    Lancet Oncol

    (2007)
  • T. Winder et al.

    Molecular predictive and prognostic markers in colon cancer

    Cancer Treat Rev

    (2010)
  • S. Popat et al.

    A systematic review and meta-analysis of the relationship between chromosome 18q genotype, DCC status and colorectal cancer prognosis

    Eur J Cancer

    (2005)
  • S. Velho et al.

    The prevalence of PIK3CA mutations in gastric and colon cancer

    Eur J Cancer

    (2005)
  • K. Nosho et al.

    PIK3CA mutation in colorectal cancer: Relationship with genetic and epigenetic alterations

    Neoplasia

    (2008)
  • S. Gupta et al.

    Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice

    Cell

    (2007)
  • W.S. Samowitz et al.

    Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer

    Gastroenterology

    (2005)
  • K. Komuro et al.

    Right- and left-sided colorectal cancers display distinct expression profiles and the anatomical stratification allows a high accuracy prediction of lymph node metastasis

    J Surg Res

    (2005)
  • D. Hanahan et al.

    Hallmarks of cancer: The next generation

    Cell

    (2011)
  • F.M. Smith et al.

    Pathological and molecular predictors of the response of rectal cancer to neoadjuvant radiochemotherapy

    Eur J Surg Oncol

    (2006)
  • J. Evans et al.

    Rectal cancer: Primary staging and assessment after chemoradiotherapy

    Semin Radiat Oncol

    (2011)
  • N. Smith et al.

    Preoperative staging of rectal cancer

    Acta Oncol

    (2008)
  • J.F. Bosset et al.

    Chemotherapy with preoperative radiotherapy in rectal cancer

    N Engl J Med

    (2006)
  • L. Blomqvist et al.

    The “good”, the “bad”, and the “ugly” rectal cancers

    Acta Oncol

    (2008)
  • K. Haustermans et al.

    The ESTRO Breur lecture 2010: Toward a tailored patient approach in rectal cancer

    Radiother Oncol

    (2011)
  • L.M. McShane et al.

    REporting recommendations for tumor MARKer prognostic studies (REMARK)

    Nat Clin Pract Oncol

    (2005)
  • E. Kapiteijn et al.

    Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer

    N Engl J Med

    (2001)
  • M.S. Roh et al.

    Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R-03

    J Clin Oncol

    (2009)
  • J.P. Gérard et al.

    Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: Results of FFCD 9203

    J Clin Oncol

    (2006)
  • C.A. Marijnen et al.

    Impact of short-term preoperative radiotherapy on health-related quality of life and sexual functioning in primary rectal cancer: Report of a multicenter randomized trial

    J Clin Oncol

    (2005)
  • K.C. Peeters et al.

    Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: Increased bowel dysfunction in irradiated patients—A Dutch colorectal cancer group study

    J Clin Oncol

    (2005)
  • H. Birgisson et al.

    Occurrence of second cancers in patients treated with radiotherapy for rectal cancer

    J Clin Oncol

    (2005)
  • H. Birgisson et al.

    Late adverse effects of radiation therapy for rectal cancer—A systematic overview

    Acta Oncol

    (2007)
  • M.M. Lange et al.

    Urinary and sexual dysfunction after rectal cancer treatment

    Nat Rev Urol

    (2011)
  • M. Braendengen et al.

    Randomized phase III study comparing preoperative radiotherapy with chemoradiotherapy in nonresectable rectal cancer

    J Clin Oncol

    (2008)
  • F.J. Fleming et al.

    Neoadjuvant therapy in rectal cancer

    Dis Colon Rectum

    (2011)
  • A. Habr-Gama et al.

    Low rectal cancer: Impact of radiation and chemotherapy on surgical treatment

    Dis Colon Rectum

    (1998)
  • A. Habr-Gama et al.

    Increasing the rates of complete response to neoadjuvant chemoradiotherapy for distal rectal cancer: Results of a prospective study using additional chemotherapy during the resting period

    Dis Colon Rectum

    (2009)
  • F. Bretagnol et al.

    Local excision of rectal tumours by transanal endoscopic microsurgery

    Br J Surg

    (2007)
  • C. Langer et al.

    Surgical cure for early rectal carcinoma and large adenoma: Transanal endoscopic microsurgery (using ultrasound or electrosurgery) compared to conventional local and radical resection

    Int J Colorectal Dis

    (2003)
  • A. Heintz et al.

    Comparison of results after transanal endoscopic microsurgery and radical resection for T1 carcinoma of the rectum

    Surg Endosc

    (1998)
  • W. Lee et al.

    Transanal endoscopic microsurgery and radical surgery for T1 and T2 rectal cancer

    Surg Endosc

    (2003)

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